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OR I G I N A L R E S E A R C H
Evaluation of α-synuclein and apolipoprotein E as
potential biomarkers in cerebrospinal fluid to
monitor pharmacotherapeutic efficacy in dopamine
dictated disease states of Parkinson’s disease andschizophrenia
This article was published in the following Dove Press journal:
Neuropsychiatric Disease and Treatment
Ashish Kumar Gupta,1
Ruchika Pokhriyal,1 Uddipan Das,1
Mohd Imran Khan,1
Domada Ratna Kumar,1 Rishab Gupta,2
Rakesh Kumar Chadda,2
Rashmi Ramachandran,3 Vinay Goyal,4
Manjari Tripathi,4
Gururao Hariprasad1
1Department of Biophysics, 2Department of
Psychiatry, 3Department of Anaesthesia,4Department of Neurology, All India Institute
of Medical Sciences, New Delhi 110029, India
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Background and objective: Dopamine plays an important role in the disease pathology of
Parkinson’s disease and schizophrenia. These two neuropsychiatric disorders represent disease end
points of the dopaminergic spectrum where Parkinson’s disease represents dopamine deficit and
schizophrenia represents dopamine hyperactivity in the mid-brain. Therefore, current treatment
strategies aim to restore normal dopamine levels. However, during treatment patients develop
adverse effects due to overshooting of physiological levels of dopamine leading to psychosis in
Parkinson’s disease, and extrapyramidal symptoms in schizophrenia. Absence of any laboratory
tests hampersmodulation of pharmacotherapy.ApolipoproteinE and α-synuclein have an important
role in the neuropathology of these two diseases. The objective of this study was to evaluate
cerebrospinal fluid (CSF) concentrations of apolipoprotein E and α-synuclein in patients with these
two diseases so that they may serve as biomarkers to monitor therapy in Parkinson’s disease and
schizophrenia.
Methods: Drug-naïve Parkinson’s disease patients and Parkinson’s disease patients treated with
dopaminergic therapy, neurological controls, schizophrenic patients treated with antidopaminergic
therapy, and drug-naïve schizophrenic patients were recruited for the study and CSF was collected.
Enzyme-linked immunosorbent assays were carried out to estimate the concentrations of apolipo-
protein E and α-synuclein. Pathway analysis was done to establish a possible role of these two
proteins in various pathways in these two dopamine dictated diseases.
Results: Apolipoprotein E and α-synuclein CSF concentrations have an inverse correlation
along the entire dopaminergic clinical spectrum. Pathway analysis convincingly establishes a
plausible hypothesis for their co-regulation in the pathogenesis of Parkinson’s disease and
schizophrenia. Each protein by itself or as a combination has encouraging sensitivity and
specificity values of more than 55%.
Conclusion: The dynamic variation of these two proteins along the spectrum is ideal
for them to be pursued as pharmacotherapeutic biomarkers in CSF to monitor pharma-
cological efficacy in Parkinson’s disease and schizophrenia.
Keywords: cerebrospinal fluid, Parkinson’s disease, schizophrenia, dopamine,
apolipoprotein E, α-synuclein, biomarkers, treatment monitoring
IntroductionParkinson’s disease is a progressive neurodegenerative disorder diagnosed based on
the presence of motor symptoms like tremor, rigidity, bradykinesia, and postural
Correspondence: Gururao HariprasadDepartment of Biophysics, All IndiaInstitute of Medical Sciences, New Delhi110029, IndiaTel +91 112 659 4029Fax +91 112 658 8663Email dr.hariprasadg@gmail.com
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http://doi.org/10.2147/NDT.S205550
instability.1 The prevalence increases with age and around
1–2% of the population over the age of 60 years is affected
by Parkinson’s disease.2,3 Schizophrenia is a chronic men-
tal disorder characterized by delusions, hallucinations, dis-
organized speech, or behavior and impaired cognitive
ability.4 The worldwide prevalence of schizophrenia is
1%.1,5,6 Dopamine is an important neurotransmitter pro-
duced in the substantia nigra and ventral tegmental regions
of the brain and its dysfunction plays a crucial role in both
Parkinson’s disease and schizophrenia.7 In Parkinson’s
disease, the decrease in dopamine in the substantia nigra
of the mid-brain caused by selective loss of dopaminergic
neurons has been implicated in disease pathology.8 On the
contrary, dopamine hyperactivity is associated with
schizophrenia.9 The treatment strategies for both the dis-
eases exploit the difference in dopamine level from the
baseline. In Parkinson’s disease, clinical intervention is
aimed at increasing the concentration of dopamine in
mid-brain.10 On the other hand, in schizophrenia, neuro-
leptics are prescribed which block dopamine receptors and
decrease overall dopamine activity.11 However, there is a
strong chance that during the treatment period patients
develop symptoms related to the other extreme of dopa-
mine spectrum, wherein Parkinson’s disease patients tend
to develop psychosis, and schizophrenia patients tend to
develop extrapyramidal side effects.12 This clinical sce-
nario is depicted by the patients recruited in this study
(Table 1).
Currently, there is no definite parameter to monitor the
treatment and assist the clinicians to modulate therapy to
avoid adverse effects. In this regard, biomarkers provide a
convenient tool that can be objectively evaluated and used as
an indicator of biological processes and pharmacologic
response in the human body.13–15 Biomarker discovery for
various diseases including neurological conditions has pro-
vided an efficient medium to monitor various disease
conditions.16–18 Despite the discovery of many protein bio-
markers for diagnosis or prognosis of Parkinson’s disease
and schizophrenia, there is no significant clinical proteomic
study to monitor drug therapy in these two diseases.19,20 The
unavailability of reliable biomarkers to monitor drug therapy
in Parkinson’s disease and schizophrenia provides opportu-
nities for clinical proteomic-based biomarker discovery in
this field. In the recent past, our group has been dedicatedly
involved in protein biomarker discovery to assess treatment
in both Parkinson’s disease and schizophrenia.21,22
Apolipoprotein E is a ligand for low-density lipoprotein
receptors and is the most important lipid transport protein Tab
le1Clinicalprofile
ofpatients
receivingpharmacologicaltherapyandshowingsideeffects
PatientID
Age
(yea
rs)
Gen
der
Clin
ical
phen
otype
Treatmen
t(G
eneric)
Sideeffects
01MA
48
Female
Schizophrenia
Olanzapine,risperidone
Tremorofhands,slow
walking,noproperbodybalance
for4years
02RA
34
Male
Schizophrenia
Olanzapine,pramipexole,haloperidol
Impairedvoice,bodystiffness,fatigue,dizziness,slow
bodymovements
for1.5
years
03MA
45
Female
Schizophrenia
Olanzapine,risperidone
Unable
towrite,tremorofhands,dizziness,poorbalance
for3years
04SH
56
Male
Schizophrenia
Olanzapine,haloperidol
Fatigue,daytimesleepiness,difficultyin
walking,jaw
stiffness
for3years
05AM
79
Male
Parkinson’sdisease
Levodopa,carbidoparopinirole,rasagiline
Depressionandvisualhallucinationsfor2years
06TA
56
Male
Parkinson’sdisease
Levodopa,carbidopa,ropinirole
Auditory
hallucinationsfor2years
07LA
58
Female
Parkinson’sdisease
Levodopa,carbidopa,ropinirole
Claustrophobia,auditory
hallucinationsanddelusionsfor2.5
years
08SI
52
Female
Parkinson’sdisease
Levodopa,carbidopa,ropinirole
Visualhallucinationsfor1year
09SA
57
Male
Parkinson’sdisease
Levodopa,carbidopa,ropinirole
Delusionandhallucinationsfor1year
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DovePressNeuropsychiatric Disease and Treatment 2019:152074
present in the brain.23 The gene is located on the chromo-
some19q13.2 with three alleles e2, e3, and e4.24 It is involved
in many complex biological processes such as regulation of
intracellular signaling, lipid metabolism, modulation of nitric
oxide synthase-mediated cell proliferation, immune system
regulation, and extracellular signaling.25–27 Apolipoprotein E
is mainly synthesized by astrocytes in the brain and is known
to be associated with various neurodegenerative disorders
including Alzheimer’s disease and Parkinson's disease.28,29
It is a predominant genetic risk factor for Parkinson’s disease
as it imparts vulnerability to early semantic memory
impairment.30 In schizophrenia, aberrant apolipoprotein E
signaling and the evidence of common receptors with schi-
zophrenia susceptibility gene, reelin, supports its role in the
disease pathology.31
α-synuclein is encoded by the SNCA gene located on the
chromosome 4q22.1.32 It is abundantly expressed in the brain
and is known to interact with lipids, presynaptic vesicles, and
plasma membrane by lipid rafts.33–35 It is a core component
of Lewy bodies which is a clinical hallmark for Parkinson’s
disease.36 In addition, point mutations in the α-synuclein
gene are known to be a risk factor for Parkinson’s disease.37
The association between α-synuclein expression and schizo-phrenia has been shown by a previous study.38 α-synuclein
expression at the mRNA level is down regulated in lympho-
cytes of schizophrenic patients.39
The intricate association of apolipoprotein E and α-synuclein, with neuropsychiatric disorders, prompted us
to study the expression of these proteins in cerebrospinal
fluid (CSF) along the clinical dopaminergic spectrum, with
a view to developing them as therapeutic efficacy monitor-
ing biomarkers in Parkinson’s disease and schizophrenia.
MethodsEthics, patient selection criteria, and
consentThe study was approved by the ethics committee of All
India Institute of Medical Sciences, New Delhi (Reference
no.: IESC/T-418/26.08.2015), and the methods followed
were as per the ethical standard formulated in the Helsinki
declaration. The Parkinson’s disease and schizophrenia
patients were screened and recruited for the study at the
Department of Neurology and Department of Psychiatry,
All India Institute of Medical Sciences, New Delhi,
respectively. The neurological control group comprised
of patients with bladder, prostate, and uterine pathologies,
who were screened at urology and gynecology clinics at
the institute. These patients were recruited for surgeries
under spinal anesthesia. Before enrolling the patients in
the study written informed consent was obtained. Briefly,
1.5 mL of CSF was collected under sterile conditions in
microfuge tubes and was centrifuged at 4°C for 5 min at
3,000 rpm. The supernatant was taken in a separate micro-
fuge tube and stored in −80°C until further experiments.
Proper care was taken while collecting the CSF samples to
avoid blood contamination, and samples with even minute
contamination with blood were excluded from the study.
Patient inclusion and exclusion criteriaInclusion criteria: The Unified Parkinson's Disease Rating
Scale was used for screening patients with Parkinson’s dis-
ease according to which a score of zero represents no dis-
ability and a score of 199 represents complete disability.40
For describing the progress of symptoms in Parkinson’s
disease patients, the Hoehn and Yahr scale was used and
was graded from stage 1 to stage 5.41 ICD 10 was used to
diagnose schizophrenia.42 Exclusion criteria: The patients
with other disease or coexisting pathology or those under
any therapeutic interventions were excluded from the study.
Enzyme-linked immunosorbent assay
(ELISA)The estimation of apolipoprotein E and α-synuclein in the
recruited patients was done using ELISA kits (Elabscience,
China). The methodology used was as per the manufacturer’s
instruction protocol. The concentrations of apolipoprotein E
and α-synuclein were extrapolated from the standard curves.
Statistical analysisThe mean concentrations for all the five groups were
plotted and a linear curve with line equations and R2
value was obtained. Correlation coefficient and p-value
(<0.05) for CSF apolipoprotein E and α-synuclein were
obtained using Student’s t-test. Receiver operating charac-
teristic (ROC) curve was obtained using GraphPad Prism
(GraphPad Prism software, San Diego, CA, USA) to
derive cut-off levels and area-under-the-curve for apolipo-
protein E and α-synuclein in Parkinson’s disease and
schizophrenia.
Pathway analysisThe entire information of genes corresponding to the
identified proteins, their related functions were obtained
from UniProt and from published literature in PubMed.
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Using this information, the proteins were analyzed for
their biological interactions in Parkinson’s disease and
schizophrenia pathways using KEGG and Schizo-Pi
database.43 For visualizing the interaction and pathways
of identified proteins and its interactors Cytoscape v2.8.0
software was used.44,45 Michigan Molecular Interactions
plugin was used to collect the human gene regulatory
interactome obtained from the public databases including
STRING, MINT, MENTHA, and HPRD and merge the
information.46–50 From this complete network, sub-net-
works for Parkinson’s disease and schizophrenia were
obtained up to the first neighboring nodes using the plugin
BiNoM v2.5. The resulting networks were merged using
Cytoscape. Venn/Euler diagram was used to analyze the
intersection between Parkinson’s disease and schizophre-
nia. The corresponding interactions of the identified pro-
teins were noted and analyzed.
ResultsClinical profileA total of 61 CSF samples of patients with Parkinson’s
disease and schizophrenia were obtained from the neurol-
ogy and psychiatry out-patient departments. The sample
group included drug- naïve patients and those treated for
Parkinson’s disease and schizophrenia and neurological
controls. The demographic profile of the patients recruited
for the study is mentioned in Table 2. The sex distribution
of the patients has fewer females as compared to males.
Also, the mean age of Parkinson’s disease patients is
almost twice that of schizophrenia patients, and the mean
age of the neurological control group is 61.4 years.
Apolipoprotein E and α-synucleinexpression in CSF of Parkinson’s diseaseand schizophreniaELISA was done to determine the CSF concentrations of
apolipoprotein E and α-synuclein across five groups; (1)
drug-naïve Parkinson’s disease, (2) treated Parkinson’s
disease, (3) neurological controls, (4) drug-naïve schizo-
phrenia and, (5) treated schizophrenia. The relationship
between apolipoprotein E and α-synuclein concentrations
and dopamine level in CSF is represented in Figure 1. It
should also be noted that the concentrations of both apo-
lipoprotein E and α-synuclein correlate with each other as
indicated by a positive correlation coefficient value of 0.5
in Figure 2. ROC curve was plotted for apolipoprotein E
and α-synuclein levels in CSF in Parkinson’s disease,
neurological control, and schizophrenia as shown in
Figure 3. Individual values corresponding to the cut-off
values, sensitivity, and specificity are given in Table 3. It
can be observed that when either of the two proteins,
apolipoprotein E and α-synuclein, were considered for
evaluation with the individual estimated cut-off values,
the sensitivity and specificity values ranged from 53.3%
to 79.3%.
Pathway analysisPathway analysis was carried out to study the interactions
of these proteins in these dopamine dictated diseases. A
total of 25 proteins were found to be directly interacting
with apolipoprotein E and α-synuclein in Parkinson’s dis-
ease, and 18 proteins were found to be directly interacting
with apolipoprotein E and α-synuclein in schizophrenia,
with 13 proteins being common amongst the two groups
(Figure 4). The functions of these proteins and their rele-
vance in this study have been delineated in Table 4. A
hypothesis has been proposed based on the ELISA results,
highlights of the pathway analysis, information from pre-
vious studies, and the same has been diagrammatically
represented in Figure 5.
DiscussionClinical profileThe incidence of Parkinson’s disease and schizophrenia
majorly affects the male population; therefore, the sex
distribution of the patients has fewer females as compared
to males.69 Secondly, the mean age of Parkinson’s disease
patients is almost double that of schizophrenia patients
because the incidence of Parkinson’s disease increases
above the age of 60 years, with only 4% of the affected
being under the age of 50 years.70 On the other hand, the
Table 2 Demographic profile of patients recruited in the study
Clinical
phenotype
Average age
(years)
Gender Total
Female Male
Parkinson 47.25 1 7 8
Parkinson Treated 52.75 3 25 28
Neurological
Control
61.4 6 9 15
Schizophrenia
Treated
27 1 5 6
Schizophrenia 25 0 4 4
Total 61
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incidence of schizophrenia occurs between 16 and 25
years.71 The mean age of the neurological control group
is 61.4 years since the patients selected as neurological
controls were those requiring surgical intervention for
urological disorders which presents around this age.72
The drug-naïve patients of Parkinson’s disease and schizo-
phrenia represent the extreme end points of dopamine
spectrum, patients who have been treated represent time
frames within this spectrum, and neurological controls
represent the mid-point of the spectrum that defines the
physiological range of dopamine.
Correlation of apolipoprotein E and α-synuclein expression in CSF of
Parkinson’s disease and schizophreniaThe concentrations of both apolipoprotein E and α-synu-clein inversely correlate with the dopamine concentrations.
It is higher in drug-naïve Parkinson’s disease patients and
linearly decreases through treated Parkinson’s disease,
neurological controls, treated schizophrenia patients and
drug-naïve schizophrenia patients. Such a relationship of
apolipoprotein E and α-synuclein concentrations with the
dopamine levels provides a window of opportunity to
modulate treatment in a way that patients do not develop
side effects. According to the ROC curve each protein,
apolipoprotein E and α-synuclein, individually or as a
combination has sensitivity and specificity values of
around 54%. This would, therefore, mean that using
these protein biomarkers for monitoring therapeutic effi-
cacy would help to reduce the number of patients affected
by drug-induced side effects in these two diseases by more
than half. These results and data are very encouraging
from a translational point of view in the field of neurop-
sychiatry. It may be noted that though the patients were
phenotypes and grouped based on certain clinical criteria,
4C
SF a
polip
opro
tein
E (p
g/m
l)
3
2
1
P PRx NC SRx S
1.80.1 CSF dopamine(pmol/ml)
4
CSF
�-s
ynuc
lein
(pg/
ml)
3
2
1
P PRx NC SRx S
1.80.1 CSF dopamine(pmol/ml)
** ****
BA
*
Figure 1 ELISA for expression of (A) apolipoprotein E and (B) α-synuclein in the cerebrospinal fluid (CSF) of Parkinson’s disease, neurological controls, and schizophrenia
patients. Clinical phenotypes comprise of Parkinson’s disease naïve (P), Parkinson’s treated (PRx), neurological controls of patients with urological and gynecological diseases
needing surgical intervention (NC), schizophrenia treated (SRx), and schizophrenia naïve patients (S). Mean ± Standard error of mean of the values is shown by horizontal
lines. The bars represent the concentrations as the average of duplicate readings of each patient sample. Trend lines of apolipoprotein E (y=−0.25x+3.78; R2=0.91) and α-synuclein (y=−0.14x+2.63; R2=0.94) across the five clinical phenotypes is shown as a blue dotted line in (A) and (B), respectively. Diagrammatic representation of the
dopamine concentration in cerebrospinal fluid (CSF) is shown along the x-axis. Concentrations of dopamine in the CSF across the clinical phenotypes has been estimated in
Gao et al and Jensen et al.47,48 * indicates statistical significance with p<0.05.
6
6 8CSF apolipoprotein E (pg/ml)
4
4
2
CSF
�-s
ynuc
lein
(pg/
ml)
2
Figure 2 Correlation analysis for apolipoprotein E expression and alpha-synuclein.
The correlation coefficient (R2) has a value of 0.5 and a statistical significance (p) of 0.05.Abbreviation: CSF, cerebrospinal fluid.
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there exists a vast heterogeneity among the patients with
respect to the age of onset of the disease, stage of the
disease, quality of drug intervention, duration of therapy,
personal habits, and habitat. This explains the subtle var-
iations in the concentrations of these two proteins.
Interaction-based pathway analysis
involving apolipoprotein E and α-synucleinin Parkinson’s disease and schizophreniaIn order to understand the role of apolipoprotein E and α-synuclein in the pathogenesis of Parkinson’s disease and schi-
zophrenia, it becomes important to study the interaction of
these proteins in the dopaminergic pathway and subsequent
cellular damage. Based on these interactions, pathway analysis
was carried out to place the observed experimental outcomes
in the right perspective. The protein interactions and cellular
mechanisms explaining the observed results are shown in
Figure 5 and is discussed below.
(A) Apolipoprotein E is the most abundant apolipopro-
tein present in the brain and is mostly synthesized by
the astrocytes.73 It is a cholesterol transport protein
which is found associated with high-density lipopro-
tein (HDL).74,75 The most common apolipoprotein E
receptor is low-density lipoprotein receptor-related
protein (LRP) which is involved in its uptake across
the plasma membrane.25 Apolipoprotein E and LRP
play a major role in cholesterol regulation which
affects processes related to abnormal turnover of
synaptic proteins.76 This turnover is a response
mechanism to counter the damage at synaptic term-
inals because of inflammation or oxidative stress,
both of which are elevated in Parkinson’s disease.77
A B
DC
Figure 3 Receiver Operating Characteristic (ROC) for cut-offs that best differentiate disease from controls. (A) Apolipoprotein E for Parkinson’s disease and neurological
control; (B) Apolipoprotein E for schizophrenia and control; (C) α-synuclein for Parkinson’s disease and control; and, (D) α-synuclein for schizophrenia and control.
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In a previous study by our group, the level of alpha-
2-macroglobulin was found to be elevated in
Parkinson’s disease as compared to schizophrenia.22
Interestingly, LRP is a common receptor for apoli-
poprotein E, alpha-2-macroglobulin and amyloid
precursor protein.78 This further strengthens the
combined role of neuronal damage induced compen-
satory response involving LRP, apolipoprotein E,
and α-synuclein.(B) α-synuclein is majorly a cytosolic protein; however,
its secretion into extracellular space has been
established.79 Extracellular α-synuclein has a hetero-
geneous population including both monomeric and
oligomeric forms that interact with Toll-like receptor
2 which is involved in its uptake.80,81 Cell surface
heparan sulfate proteoglycans are also known to be
involved in apolipoprotein E-mediated uptake of α-synuclein.82 α-synuclein binds to cholesterol and mod-
ulates α-synuclein aggregation and its association withHDL.83–85 Apolipoprotein E increases aggregation of
α-synuclein which is a known component of Lewy
bodies and promotes neurodegeneration.86
(C) α-synuclein also interacts with protein phosphatase
2A (PP2A) and increases its activity, activated PP2A
is involved in dephosphorylation of tyrosine hydro-
xylase, which is a critical enzyme in dopamine meta-
bolism, therefore leads to a reduction of dopamine
levels.66 α-synuclein is also known to bind to
Table 3 Pharmacotherapeutic monitoring value of Apolipoprotein E and α-synuclein in Parkinson’s disease and schizophrenia
Biomarker Cut-off values to differentiate neurological controls from the
disease
Parameters
Sensitivity
(%)
Specificity
(%)
Apolipoprotein E >3.4 pg (Parkinson’s disease) 41.7 86.7
Apolipoprotein E <2.6 pg (Schizophrenia) 50.0 60.0
α-synuclein >2.2 pg (Parkinson’s disease) 55.6 80.0
α-synuclein <1.9 pg (Schizophrenia) 20.0 93.3
Apolipoprotein E or α-
synuclein
>3.4 pg (Parkinson’s disease) 79.3 66.6
>2.2 pg (Parkinson’s disease)
Apolipoprotein E or α-
synuclein
<2.6 pg (Schizophrenia) 60.0 53.3
<1.9 pg (Schizophrenia)
Figure 4 Pathway analysis shows apolipoprotein E and alpha-synuclein, and their respective interactions. apolipoprotein E and alpha-synuclein are shown in white nodes,
interacting nodes in Parkinson’s disease pathway are highlighted in green, interacting nodes in schizophrenia pathway are highlighted in pink, and nodes that common to both
the groups are highlighted in yellow. Those nodes in the schizophrenia group that have four or more than four interactions are indicated in larger size boxes and those less
than four are indicated by smaller boxes. All the interactions are shown by gray lines.
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Tab
le4Interactionsofapolipoprotein
Eandα-synuclein
inthepathogenesisofParkinson’sdiseaseandschizophrenia
Pro
tein
Function
Relev
ance
inthis
study
Referen
ces
Voltage-dependentanion
channels
●Transport
ATP,sm
allmetabolitesacross
theouter
mitochondrialmembrane
●Calcium
signalingpathway
●Cholesterolmetabolism
●Parkinson’sdisease
●Over-expressionofα-synuclein
causesthedegenerationofdopam
inergic
neuronsthrough
and
interactionwithmitochondrialVDAC,whichleadsto
mPTPactivation,mitochondrialuncoupling,
andcelldeath
51–57
NADH:ubiquinoneoxi-
doreductasesubunitS3
●Partofthemultisubunit
NADH:ubiquinoneoxi-
doreductase(complexI)
●Involvedin
transfers
electronsfrom
NADH
tothe
respiratory
chain
●Directlyinvolvedin
electrontransferandcoupling
●IncreasesROSgenerationcausesoxidativestress
andcellulardam
age
●IncreasedATPproductionorelevatedcomplexIactivity
58
Synphilin-1
●In
neuronal
tissueplays
arole
intheform
ationof
cytoplasm
icinclusionsandneurodegeneration
●Synphilin-1
interactswithalpha-synuclein
andpromote
theform
ationoflewybody
59,60
ADP-ribosylationfactor
GTPase-activatingprotein
1
●Involvedin
membranetraffickingvesicletransport.
●LRRK2-dependentneurodegenerationin
Parkinson
61
Protein
phosphatase-2A
●Role
indirecting
signaling
toward
survival
or
degeneration
●Inhibitionoftyrosinehydroxylase
●α-
synuclein
norm
ally
stimulatesPP2A
activity
andreducesphosphorylationoftyrosinehydro-
xylasethrough
regulatingthemethylationofPP2A
62–64
Sodium-dependentdopa-
minetransporter
●Term
inatestheactionofdopam
inebyitshighaffi-
nitysodium-dependentreuptakeinto
presynaptic
term
inals
●Alongwithα-synuclein
itform
scomplexthat
facilitatesthemembraneclusteringofdopam
ine
transportertherebyacceleratingdopam
ine-inducedapoptosis
65,66
Microtubule-associated
protein
tau
●Promotesmicrotubule
assemblyandstability
●Maintenance
ofneuronalpolarity
●Alongwith-α
synuclein
itaggregate
toform
lewybody
67
AKT_Serine/threonine
kinase-1
●TORsignaling
●Regulate
many
processes
including
cell
survival,
growth,apoptosis
●Aktinhibitioncause
decreasein
receptorlevel,hence
disruptingthenorm
alfeedbackmechanism
ofdopam
ineproduction
68
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tyrosine hydroxylase gene promoter and down reg-
ulate its expression.87 This is substantiated by the
fact that there is a decreased level of tyrosine hydro-
xylase mRNA in Parkinson’s disease.88
(D) The inverse relationship between apolipoprotein E and
α-synuclein to the dopamine spectrum represented by
clinical phenotypes including Parkinson’s disease, neu-
rological controls, and schizophrenia is very interesting.
β2-adrenergic receptor agonists (β2AR) are known to
mimic endogenous catecholamines like dopamine, nor-
epinephrine, and epinephrine.89 β2AR activation
decreases histone acetylation of the α-synuclein gene
and suppresses its transcription.90 α-synuclein in asso-
ciationwithATP-binding cassette sub-familyAmember
1 (ABCA1), a plasma membrane transporter protein, is
known to increase the cholesterol efflux mechanism.91
In the brain, deficiency of ABCA1 which is required for
cholesterol efflux to apolipoprotein E leads to reduced
lipidation and an overall decrease of apolipoprotein E
levels.92
(E) In addition, psychotropic drugs up-regulate the
expression of apolipoprotein E by activation of sterol
regulatory element-binding protein transcription fac-
tors through an intracellular oxysterol sensor, liver X-
receptor.93 Liver X-receptor has been shown to
positively regulate α-synuclein expression.94 On the
contrary, levodopa-induced lipogenesis inhibition has
only been shown in certain non-neurological tissues.95
(F) Oxidative stress is another important parameter that
regulates apolipoprotein E and α-synuclein in
Parkinson’s disease and schizophrenia. Oxidative stress
is known to be elevated in Parkinson’s disease and is
decreased in schizophrenia.96 The increased formation
of reactive oxygen species in dopaminergic neurons in
Parkinson’s disease leads to the formation of cholesterol
aldehydes that enable α-synuclein aggregation, leading
to a pathologic cycle.97 Alterations in lipid metabolism
have an important role in the pathogenesis of
Parkinson’s disease since there is direct cross-talk
between lipids and α-synuclein, influencing both lipid
metabolism and α-synuclein aggregation.98,99 In the
brain, apolipoprotein E is expressed by astrocytes and
perivascular cells under normal conditions. However, it
has also been found to be intra-neuronally expressed.
Such a pattern of apolipoprotein E expression is seen
when neurons are under stress conditions.100 Increased
apolipoprotein E formation under such conditions can
affect neuronal survival due to the formation of a C-
terminal truncated form which causes mitochondrial
impairment in neurons.101
ConclusionApolipoprotein E and α-synuclein CSF concentrations
have an inverse correlation along the entire dopaminergic
clinical spectrum comprising of Parkinson’s disease and
schizophrenia. Each protein by itself or as a combination
α-syn(protofibrils)
α-syn(protofibrils)
α-syn(protofibrils)
TLR2 TLR2 TLR2
HSPGHSPG
A B C
HSPG
P2A P2A P2A
L B
LDLDL RP
ApoEApoE
ApoE
Inflammation
Oxidative stress
L RP L RP
TH TH TH
LD
Dopamine DopamineDopamine
α-syn(fibrils)
Ty Ty Ty
L-DOPA L-DOPA L-DOPA
Figure 5 Diagrammatic representation of neuronal synapse depicting experimental result-based hypotheses that explain molecular events in Parkinson’s disease,
neurological controls, and schizophrenia.
Abbreviations: HSPG, Heparan Sulphate Proteo-Glycan; TLR2, Toll-Like Receptor 2; LRP, Low density lipid Receptor Protein; L-DOPA, Levo-Dopa; P2A, phosphatase 2A;
LB, Lewy body; LD, L-decarboxylase; TH, tyrosine hydroxylase; Ty, tyrosine.
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has the ability to differentiate either of the pathological
states from the physiological state. Pathway analysis sup-
ports the mechanism of coregulation in the pathogenesis of
the two diseases. The dynamic variation of these two
proteins along the spectrum is ideal for them to be pursued
as pharmacotherapeutic biomarkers in CSF to monitor
pharmacological efficacy in Parkinson’s disease and schi-
zophrenia with a reasonable accuracy. Outcome of this
study will be helpful for the clinicians and patients to
monitor pharmacotherapy and make informed treatment
decisions in Parkinson’s disease and schizophrenia.
AcknowledgmentsAn abstract of this paper titled ‘Evaluation of apolipopro-
tein E and α-synuclein as potential biomarkers in CSF to
monitor pharmaco-therapeutic efficacy in dopamine dic-
tated disease states of Parkinson’s disease and schizophre-
nia’ was published in the 2019 Science Program, by the
American Academy of Neurology as a part of the Annual
Meeting held in Philadelphia, PA, USA, in May 2019
((http://indexsmart.mirasmart.com/AAN2019/PDFfiles/
AAN2019-000045.pdf).
GH acknowledges Department of Science and
Technology, Government of India for the grant SO/BB-
0122/2013 (D-348). The work was partly carried out at
the Proteomics Division at Central Core Research
Facility at AIIMS, New Delhi, India.
DisclosureThe authors report no conflicts of interest in regard to this
work.
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